Self-sustained release immune adjuvant suspension, preparation method therefor, and use thereof

Abstract

The present application relates to a self-sustained release immune adjuvant suspension comprising microparticles composed of a lipid soluble immune adjuvant and a surfactant, the balance being a dispersant, wherein the lipid soluble immune adjuvant is coated with the surfactant to form the microparticles which are dispersed in the dispersant to form a suspension. The self-sustained release immune adjuvant suspension can be retained in a tumor for a long time and can maintain a sustained release property, and can also inhibit the growth of distal metastatic tumors and reduce the probability of tumor recurrence by means of an immune response. The present application further provides a preparation method for a self-sustained release immune adjuvant suspension, and use of the self-sustained release immune adjuvant suspension in a sensitizing formulation used for tumor therapies, such as, radiotherapy, chemotherapy, or thermotherapy.

1 - 45 . (canceled) 
     
     
         46 . A self-sustained release immune adjuvant suspension composed of a lipid soluble immune adjuvant and a surfactant, the balance being a dispersing medium, wherein the lipid soluble immune adjuvant is coated with the surfactant to form microparticles which are dispersed in the dispersing medium to form the suspension. 
     
     
         47 . The self-sustained release immune adjuvant suspension according to  claim 46 , wherein the lipid soluble immune adjuvant comprises at least one of imiquimod (R837), resiquimod (R848) or glucopyranoside lipid A (MPLA). 
     
     
         48 . The self-sustained release immune adjuvant suspension according to  claim 46 , wherein the particles of the lipid soluble immune adjuvant are core-shell composite with a particle size of 0.5 to 5 microns. 
     
     
         49 . The self-sustained release immune adjuvant suspension according to  claim 46 , wherein the surfactant is a surfactant with a higher fatty acid chain; wherein the surfactant with a higher fatty acid chain comprises an anionic surfactant; wherein the anionic surfactant comprises at least one of sodium oleate, sodium dodecyl sulfate, sodium stearate, sodium N-lauroyl sarcosinate, sodium cocoyl methyl taurate, sodium N-lauroyl glutamate, sodium lauryl polyoxyethylene ether carboxylate, and dodecyl phosphate; wherein the surfactant with a higher fatty acid chain comprises an amphiphilic ionic surfactant; wherein the surfactant with a higher fatty acid chain comprises a phospholipid ionic surfactant; wherein the phospholipid ionic surfactant comprises at least one of lecithin, soybean phospholipid, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol. 
     
     
         50 . The self-sustained release immune adjuvant suspension according to  claim 46 , wherein a hydrophobic structural moiety of the surfactant comprises not less than 20 oxypropylene units; wherein the surfactant comprises at least one of Poloxamer 188, Poloxamer 237, Poloxamer 338, and Poloxamer 407. 
     
     
         51 . The self-sustained release immune adjuvant suspension according to claim  46 , wherein a hydrophobic structural moiety of the surfactant comprises one or more hydrocarbon chains with a total of not less than 15 carbon atoms; wherein the surfactant comprises at least one of sorbitan sesquioleate, soybean phospholipid, glyceryl monostearate, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, sorbitan stearate (Span 60), stearate, vitamin E polyethylene glycol succinate, polyoxyethylene alkyl ether, polyoxyethylene stearate, polyoxyl (40) stearate, sucrose stearate, a polyoxyethylenated castor oil derivative, cetomacrogol 1000, and lecithin. 
     
     
         52 . The self-sustained release immune adjuvant suspension according to  claim 46  comprising an imiquimod suspension formulation comprising: imiquimod microparticles, a surfactant with a higher fatty acid chain, and a dispersing medium. 
     
     
         53 . The self-sustained release immune adjuvant suspension according to  claim 52  wherein the concentration of the imiquimod microparticles is 1 to 18 mg/mL, and a mass ratio of the surfactant with a higher fatty acid chain to the imiquimod microparticles is 0.025 to 3:1. 
     
     
         54 . A self-sustained release immune adjuvant composition comprising a first composition and a second composition, wherein the first composition is composed of a lipid soluble immune adjuvant and a surfactant, the balance being a dispersant, wherein the lipid soluble immune adjuvant is coated with the surfactant to form microparticles which are dispersed in the dispersant to form a suspension; and the second composition comprises lyophilized powder formed from a soluble alginate and a protective filler. 
     
     
         55 . The self-sustained release immune adjuvant composition according to  claim 54 , wherein the lipid soluble immune adjuvant comprises at least one of imiquimod (R837), resiquimod (R848) or glucopyranoside lipid A (MPLA). 
     
     
         56 . The self-sustained release immune adjuvant composition according to  claim 54 , wherein a hydrophobic structural moiety of the surfactant comprises not less than 20 oxypropylene units; the self-sustained release immune adjuvant composition according to claim  10 , wherein the surfactant comprises at least one of Poloxamer 188, Poloxamer 237, Poloxamer 338, and Poloxamer 407. 
     
     
         57 . The self-sustained release immune adjuvant composition according to  claim 54 , wherein a hydrophobic structural moiety of the surfactant comprises one or more hydrocarbon chains with a total of not less than 15 carbon atoms; the surfactant comprises at least one of sorbitan sesquioleate, soybean phospholipid, glyceryl monostearate, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, sorbitan stearate (Span 60), stearate, vitamin E polyethylene glycol succinate, polyoxyethylene alkyl ether, polyoxyethylene stearate, polyoxyl (40) stearate, sucrose stearate, a polyoxyethylenated castor oil derivative, cetomacrogol 1000, and lecithin. 
     
     
         58 . The self-sustained release immune adjuvant composition according to  claim 54 , wherein the dispersant is water or normal saline. 
     
     
         59 . The self-sustained release adjuvant composition according to  claim 54 , wherein the protective filler is mannitol or lactose. 
     
     
         60 . The self-sustained release immune adjuvant composition according to  claim 54 , wherein the second composition further comprises a pH regulator. 
     
     
         61 . Use of the self-sustained release immune adjuvant suspension according to  claim 46  or the self-sustained release immune adjuvant composition according to  claim 46  in preparation of an anti-tumor combinational immunotherapeutic formulation. 
     
     
         62 . The use according to  claim 61 , wherein the self-sustained release immune adjuvant comprises an imiquimod suspension formulation. 
     
     
         63 . The use according to  claim 61 , wherein the imiquimod suspension formulation is pre-mixed with a platinum-based chemotherapeutic drug to assist a sustained release of the platinum-based chemotherapeutic drug. 
     
     
         64 . The use according to  claim 61 , wherein the imiquimod suspension formulation is pre-mixed with an anthracycline-based chemotherapeutic drug to assist a sustained release of the anthracycline-based chemotherapeutic drug. 
     
     
         65 . Use of the self-sustained release immune adjuvant suspension according to  claim 46  or the self-sustained release immune adjuvant composition according to  claim 46  in preparation of a radiotherapy sensitizing agent, a chemotherapy sensitizing agent, a thermotherapy sensitizing agent, or an ethanol ablation sensitizing agent.